Madrid, 26-27 de enero de 2013
Carlos Panizo
Servicio de Hematología. Clínica Universidad de Navarra
Tratamiento del LNH folicular en recaída
Bendamustine-Rituximab (BR) Replaces R-CHOP as “Standard of
Care” in the Treatment of Indolent Non-Hodgkin’s Lymphoma in
German Haematology Outpatients Centres
.
Knauf W, et al. ASH 2012:Abstract 3666
BR es el tratamiento sistémico utilizado con más frecuencia en LNHi en los centros “outpatient”
en Alemania.
El esquema R-CHOP ya no se considera como el “standard of care” para los pacientes con
LNHi.
Los resultados de los ensayos clínicos se trasladan con velocidad a la práctica clínica habitual.
Patterns of Delivery of Chemoimmunotherapy to patients with
Follicular Lymphoma in the United States: Results of the National
Lymphocare Study
.
Martin P, et al. ASH 2012:Abstract 3702
BR es muy poco utilazado en este entorno.
Como los esquemas R-CHOP, R-CVP y R-
Fludarabina son los más usados en primera
línea, BR es una muy buena aproximación
para la segunda línea en estos pacientes.
FDG-PET/CT Early After 90Y-Ibritumomab Tiuxetan
Therapy Predicts Outcome in Relapsed or Refractory
Indolent B-Cell Lymphoma .
Okada M, et al. ASH 2012:Abstract 3648
El PET-FDG/CT realizado 2 semanas después de la administración del 90Y Ibritumomab
Tiuxetan predice mejor la SLP en LNHi en recaída o refractario
• N: 6 pts con Linfoma Folicular
• 8 FL, 6 tFL, 6 germline
•Secuenciación del genoma completo
• Número de tratameintos: 2-6;
• Número de recaídas: 1-6
• Mediana de tiempo a transformación: 8,6 años
Whole Genome Sequencing in Sequential Biopsies Reveals the Genetic
Evolution of Follicular Lymphoma to Transformed Follicular Lymphoma
.
Okosun J, et al. ASH 2012:Abstract 145
Media de mutaciones somáticas/tumor:
72 (range: 41-143) con mayor frecuencia
en tFL (mediana: FL 64.8; tFL 83.6), lo
que indica evolución genética con la
progresión.
Todas las biopsias mostraron mutaciones
en MLL2 (gen implicado en metilación de
histonas) También mutaciones en la vía
de NF-kB, receptor de la señal de célula
B, desarrollo B, reparación DNA,
regulación de apoptosis.
Rituximab, Bendamustine, Mitoxantrone, Dexamethasone (R-BMD) in Patients
with Follicular Lymphoma in Relapse or Refractory to First-Line Treatment with
Immunochemotherapy. R-BMD Geltamo 08 Trial
Peñalver J, et al. ASH 2012: Abstract 1639
N = 60
Rituximab, Bendamustine, Mitoxantrone, Dexamethasone (R-BMD) in Patients
with Follicular Lymphoma in Relapse or Refractory to First-Line Treatment with
Immunochemotherapy. R-BMD Geltamo 08 Trial
Peñalver J, et al. ASH 2012: Abstract 1639
Rituximab, Bendamustine, Mitoxantrone, Dexamethasone (R-BMD) in Patients
with Follicular Lymphoma in Relapse or Refractory to First-Line Treatment with
Immunochemotherapy. R-BMD Geltamo 08 Trial
Peñalver J, et al. ASH 2012: Abstract 1639
Outcome of BEAM-Autologous and BEAM-Alemtuzumab Allogeneic
Transplantation in Relapsed Advanced Stage Follicular Lymphoma
Noriega V, et al. ASH 2012:Abstract 2022
Lunning MA, et al. ASH 2012:Abstract 3136
The management of relapsed/refractory FL
remains a clinically complex topic.
Remission duration of ≤ 12 months prior to
re-induction chemotherapy is suggestive of
inferior disease control with HDT-ASCR.
Given the relatively unfavorable pre-
transplant characteristics of the alloSCT
cohort, FL appears to be exquisitely
sensitive to an allogeneic effect. TRM
continues to limit the benefit of alloSCT
Remission Duration ≤ 12 Months for Early Relapsed and Refractory Follicular
Lymphoma Is Predictive of Early Failures Post-High Dose Therapy and
Autologous Stem Cell Rescue
Blood and Lymphatic Microenvironment as Prognostic Factor in
Follicular Lymphoma
Nesterova ES, et al. ASH 2012:Abstract 2696
Rituximab +/- Bevacizumab for Patients with Previously Treated Follicular
Non-Hodgkins Lymphoma: A Randomized Phase II Trial of the Sarah Cannon
Research Institute
Hainsworth JD, et al. ASH 2012:Abstract 2749
Avastin
unión al factor de crecimiento del endotelio vascular (VEGF)
Lenalidomide Is Effective in Heavily Pretreated Non Hodgkin Lymphoma
(NHL): Analysis of a Retrospective Data Collection
Rigacci L, et al. ASH 2012:Abstract 3964
Phase 1b Study of TRU-016, an Anti-CD37
SMIPTM Protein, in Combination with
Rituximab and Bendamustine in Relapsed
Indolent Lymphoma
Pharmacokinetic and Pharmacodynamic
Analysis of Ocaratuzumab in 50 Patients with
Relapsed Follicular Lymphoma and Low-
Affinity FcγRIIIa (CD16a) Polymorphisms)
An Open-label, Phase I Study of R-CVP in
Combination With Inotuzumab Ozagamicin
in Patients With CD22-positive B-cell non-
Hodgkin’s Lymphoma: Preliminary Safety
and Efficacy Data
Phase II Safety and Efficacy Study of CT-011,
a Humanized Anti-PD-1 Monoclonal
Antibody, in Combination with Rituximab in
Patients with Relapsed Follicular Lymphoma
Bispecific SCORPION™ Molecules
Effectively Redirect T-Cell Cytotoxicity
Toward CD19-Expressing Tumor Cells
Immunotherapy with LAK Cells and Anti-
CD20 Monoclonal Antibodies for Follicular
Lymphoma: Enhanced Antibody-Dependent
Cell Cytotoxicity of LAK Cells in Association
with GA101 Rather Than Rituximab
Phase 1b Study of TRU-016, an Anti-CD37 SMIPTM Protein, in Combination
with Rituximab and Bendamustine in Relapsed Indolent Lymphoma
.
Gopal AK, et al. ASH 2012:Abstract 3678
CD37 – tetraspanin presente en la superficie celular en linfocitos B normales y neoplásicos.
Miembro de la superfamilia de proteínas transmembrana 4.
Co-associada con HLA-DR, CD81 (TAPA-1), CD82, CD53.
Expresada por tumores de células B.
Función desconocida
Papel en la interacción B/T Posible papel en la proliferación T Posible participación en regulación de
producción de IL6 por células dendríticas
Phase 1b Study of TRU-016, an Anti-CD37 SMIPTM Protein, in Combination
with Rituximab and Bendamustine in Relapsed Indolent Lymphoma
.
Gopal AK, et al. ASH 2012:Abstract 3678
Bien tolerado: MTD no alcanzada
Clínicamente activo:
ORR 100% a 20 mg/kg
ORR 83% todos los pacientes
CR 33% todos los pacientes
F
c
F
v VL
VH
CL
CH2
CH3
CH1
MW 150
kDa
VL
VH
Hinge
Linker
TRU-016 MW ~105
kDa
Antibody
huFc
ADAPTIRTM (Modular Protein Technology)
Targeting CD37
Pharmacokinetic and Pharmacodynamic Analysis of Ocaratuzumab in 50
Patients with Relapsed Follicular Lymphoma and Low-Affinity FcγRIIIa
(CD16a) Polymorphisms
.
Du M, et al. ASH 2012:Abstract 2750
An Open-label, Phase I Study of R-CVP in Combination With Inotuzumab
Ozagamicin in Patients With CD22-positive B-cell non-Hodgkin’s Lymphoma:
Preliminary Safety and Efficacy Data
Ogura M, et al. ASH 2012:Abstract 1633
Phase II Safety and Efficacy Study of CT-011, a Humanized Anti-PD-1
Monoclonal Antibody, in Combination with Rituximab in Patients with
Relapsed Follicular Lymphoma
Westin JR, et al. ASH 2012:Abstract 793
● Fase II
● N=30 LF recaídos (1-4 Ttos previos) RTX sensibles
● Criterios de inclusión habituales
CT-011 3 mg/Kg x4 dosis + RTX
1 4 8
Evaluación
32 28 24 20 16 12 2
… hasta 12
CT-011 + RTX RTX
ORR 66% 40%
CR 52% 11%
• La expresión de programmed death (PD)-1, un
receptor coinhibidor, está aumentada en las células
T intratumorales en LF.
• CT-011 (pidilizumab), Ac monoclonal anti-PD-1
bloquea la vía PD-1/PD-ligand pudiendo
incrementar la función antitumoral de linfoitos T y
NK.
• Rituximab actúa vía ADCC
Bispecific SCORPION™ Molecules Effectively Redirect T-Cell Cytotoxicity
Toward CD19-Expressing Tumor Cells
Chenault RA, et al. ASH 2012:Abstract 3722
Immunotherapy with LAK Cells and Anti-CD20 Monoclonal Antibodies for
Follicular Lymphoma: Enhanced Antibody-Dependent Cell Cytotoxicity of
LAK Cells in Association with GA101 Rather Than Rituximab
Panizo C, et al. ASH 2012:Abstract 4881
% C
ito
toxic
ida
d
LAK cells generated from peripheral blood lymphocytes by culture with IL-2 in patients with LF show
a higher cytotoxic activity than naive lymphocytes. The observed cytotoxic capacity of these LAK
cells against a CD20 positive cell line (CRL-1596) is enhanced by the addition of anti-CD20 mAbs.
Interestingly, GA101 was consistently more effective than rituximab in enhancing the cytotoxic
capacity of LAK cells.
Combinations of the Phosphatidylinositol
3-Kinase-Delta (PI3Kδ) Inhibitor Gs-1101
(CAL-101) with Rituximab and/or
Bendamustine Are Tolerable and Highly
Active in Previously Treated, Indolent Non-
Hodgkin Lymphoma: Results From a Phase
I Study
A Phase I Trial of the Bruton’s Tyrosine
Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765),
in Combination with Rituximab (R) and
Bendamustine in Patients with
Relapsed/Refractory Non-Hodgkin’s
Lymphoma (NHL)
Clinical Safety and Activity in aPhase 1
Trial of IPI-145, a Potent Inhibitor of
Phosphoinositide-3-Kinase-,Y, in Patients
with Advanced Hematologic Malignancies
The Bruton’s Tyrosine Kinase Inhibitor
Ibrutinib (PCI-32765) Is Active and Tolerated
in Relapsed Follicular Lymphoma
The Bruton’s Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Is Active and
Tolerated in Relapsed Follicular Lymphoma
Fowler NH, et al. ASH 2012:Abstract 156
● Fase I
● Búsqueda DMT
● LNH indolentes recaidos
● LF N=14
Cohort Ibrutinib dose (mg)
orally
28-day on/7-day off 1,25 mg/kg
28-day on/7-day off
28-day on/7-day off
28-day on/7-day off
28-day on/7-day off 12,5 mg/kg
Continuous 8,3 mg/kg
Continuos 560 mg fija
TOXICIDAD:
Buena tolerancia. MTD no alcanzada
AEs en ≥ 25% included: diarrea (50%), fatigue
(44%), naúseas (38%), tos (31%) y mialgias (25%).
Hubo 1 Grade 4: hypokalemia.
EFICACIA:
14 pts con LF, 11 evaluables
(>2,5 mg/kg)
ORR: 54.5% (3 CRs, 3 PRs)
Duración de respuesta
(DOR) 12.3 meses.
Mediana PFS 13.4 meses.
2 pts siguieron Tto.: +25 y
+29 meses
Clinical Safety and Activity in a Phase 1 Trial of IPI-145, a Potent Inhibitor of
Phosphoinositide-3-Kinase-,Y, in Patients with Advanced Hematologic
Malignancies
Flinn IW, et al. ASH 2012:Abstract 3663
IPI-145 es un potente inhibidor a dosis < 15 mg BID.
Dosis mayores potencian la inhibición.
SAEs más frecuentes: citopenias, elevación ALT/AST
Clínicamente activo:
Respuestas en iNHL con dosis < 50 mg BID
A Phase II Multicenter Study of the Histone
Deacetylase Inhibitor (HDACi) Abexinostat
(PCI-24781) in Relapsed/ Refractory
Follicular Lymphoma (FL) and Mantle Cell
Lymphoma (MCL)
Abexinostat (S78454 / PCI-24781), an Oral
Pan-Histone Deacetylas (HDAC) Inhibitor in
Patients with Refractory or Relapsed
Hodgkin's Lymphoma, Non-Hodgkin
Lymphoma and Chronic Lymphocytic
Leukemia. Results of a Phase I Dose-
Escalation Study in 35 Patients
Abexinostat (S78454 / PCI-24781), an Oral Pan-Histone Deacetylas (HDAC)
Inhibitor in Patients with Refractory or Relapsed Hodgkin's Lymphoma, Non-
Hodgkin Lymphoma and Chronic Lymphocytic Leukemia. Results of a Phase I
Dose-Escalation Study in 35 Patients
Morschhauser F, et al. ASH 2012:Abstract 3643
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